Compositions and uses of amidine derivatives

Abstract

Use of a compound of formula (I): wherein A, X, Y, R1 and R2 as defined herein, in treating hereditary angioedema is disclosed. A composition containing the compounds, a polar organic solvent or a mixture thereof; and optionally a co-solvent, is also disclosed.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application is a national stage under 35 U.S.C. 371 of International Application PCT / US2015 / 046578, filed on Aug. 24, 2015 (currently published). International Application no. PCT / US2015 / 046578 cites the priority of U.S. patent application No. 62 / 040,836, filed Aug. 22, 2014.FIELD OF THE INVENTION[0002]This invention relates to novel uses of amidine derivatives. It also relates to novel compositions containing amidine derivatives and their use in the treatment of a range of conditions.BACKGROUND TO THE INVENTION[0003]Hereditary angioedema (HAE) is a serious and potentially life-threatening rare genetic illness, caused by mutations in the C1-esterase inhibitor (C1INH) gene, located on chromosome 11q. HAE is inherited as an autosomal dominant condition, although one quarter of diagnosed cases arise from a new mutation. HAE has been classed as an orphan disease in Europe, with an estimated prevalence of 1 in 50,000. Individuals with HAE...

AI Technical Summary

Problems solved by technology

Attacks vary in frequency, severity and location and can be life-threatening.

Laryngeal attacks, with the potential for asphyxiation, pose the greatest risk.

Abdominal attacks are especially painful, and often result in exploratory procedures or unnecessary surgery.

Facial and peripheral attacks are disfiguring and debilitating.

Older non-specific treatments including androgens and antifibrinolytics are associated with significant side effects, particularly in females.

There is currently no specific targeted oral chronic therapy for HAE.

In the pharmaceutical arts, it is known that a number of APIs cannot be administered effectively by the oral route.

However, non-oral administration poses a disadvantage for the patient as well as healthcare providers, and for this reason, it is important to develop alternative routes of administration for such compounds, such as oral routes of administration.

While the oral route of administration is the most convenient for the patient and the most economical, designing formulations for administration by the oral route involves many complications.

Of the four classes, APIs falling into Class IV are the most difficult to formulate into a formulation for administration by the oral route that is capable of delivering an effective amount of the API as problems of both solubility and permeability must be addressed (note the BDDCS does not inherently address chemical stability).

The compounds are poorly soluble in aqueous and physiological fluids, and are poorly permeable as demonstrated by oral dosing in rats and in vitro experiments with Caco-2 cells.

Furthermore, the compounds described in Zhang et al., including 3-[2-(4-carbamimidoyl-phenylcarbamoyl)-5-methoxy-4-vinyl-phenyl]-6-(cyclopropylmethyl-carbamoyl)-pyridine-2-carboxylic acid, exhibit poor stability with respect to oxidation in air, to light (photodegradation) and in aqueous and physiological fluids, as well as to elevated temperatures.

Therefore, the compounds described by Zhang et al. including, but not limited to, 3-[2-(4-carbamimidoyl-phenylcarbamoyl)-5-methoxy-4-vinyl-phenyl]-6-(cyclopropylmethyl-carbamoyl)-pyridine-2-carboxylic acid, not only exhibit poor solubility and permeability characteristics, but also poor stability characteristics.

As a result, such compounds are predicted to be especially difficult to formulate into an effective, orally deliverable pharmaceutical composition that is capable of delivering an effective amount of the compound to a subject.

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